The Duplex Interaction of Microbiome with Chemoradiation and Immunotherapy: Potential Implications for Colorectal Cancer

  • Azhar Saeed
  • Fariha Eshrat
  • Shahid Umar
  • Anwaar SaeedEmail author
Basic Science Foundations in Colorectal Cancer (S Umar, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Basic Science Foundations in Colorectal Cancer


Purpose of review

Gut microbiota has the ability to modify the metabolism of wide array of therapeutic drugs. Current treatment modalities used in colorectal cancer have a narrow therapeutic index with a side effects profile that decreases tolerance to these treatments and adversely affects treatment outcome. Harnessing the gut microbiota ability to modify oncotherapeutic drugs metabolism and hence efficacy, could be potentially used to improve treatment outcomes in colorectal cancer patients. This review will shed lights on important findings from recent microbiome interaction studies which would hopefully serve as a useful tool to guide future translative colorectal cancer research.

Recent findings

Recent advances in microbiome studies have revealed an interesting aspect of gut microbes’ carcinogenic properties in dysbiotic gut environment. Microbiota niche in colorectal cancer can also modify efficacy and toxicity profile of different oncotherapeutic treatment modalities from chemoradiotherapy to immunotherapy. Conversely, each of these treatment modalities has numerous effects on the gastrointestinal flora, causing changes in the gut microbial community that affects host morbidity and mortality.


Symbiotic gut microbiota is an incredible functioning organ that maintains essential aspects of our homeostasis and immunity. According to the recent body of literature, they also can modify efficacy of many therapeutic drugs including oncotherapy. Considering that unexplainable variable treatment outcomes as well as variable tolerance to treatment have been observed in colorectal cancer patients, studying gut microbiota modulatory effects on oncotherapy might be a feasible approach to explain this phenomenon.


Chemotherapy Radiotherapy Chemoradiation Cancer Oncology Colon Microbiome Microbiota Pharmacomicrobiomics Gastrointestinal Oncotherapy 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Rizkallah MR, Saad R, Aziz RK. The human microbiome project, personalized medicine and the birth of pharmacomicrobiomics. Curr Pharmacogenomics Pers Med. 2010;8:182–93.CrossRefGoogle Scholar
  2. 2.
    Evans JM, Morris LS, Marchesi JR. The gut microbiome: the role of a virtual organ in the endocrinology of the host. J Endocrinol. 2013;218:R37–47.CrossRefGoogle Scholar
  3. 3.
    Claesson MJ, Cusack S, Sullivan O, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci. 2011;108:4586–91.CrossRefGoogle Scholar
  4. 4.
    Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800–12. Scholar
  5. 5.
    • Gagnière J, Raisch J, Veziant J, et al. Gut microbiota imbalance and colorectal cancer. World J Gastroenterol. 2016;22(2):501–18 Comprehensive review article highlighting the impact of Gut microbiota on colon cancer development and outcome.CrossRefGoogle Scholar
  6. 6.
    Haiser HJ, Turnbaugh PJ. Developing a metagenomic view of xenobiotic metabolism. Pharmacol Res. 2013;69:21–31.CrossRefGoogle Scholar
  7. 7.
    Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.CrossRefGoogle Scholar
  8. 8.
    Burdak-Rothkamm S, Rothkamm K. Radiation-induced bystander and systemic effects serve as a unifying model system for genotoxic stress responses. Rev Mutat Res. 2018;778(4):13–22.CrossRefGoogle Scholar
  9. 9.
    Zitvogel L, Galluzzi L, Viaud S, Vétizou M, Daillère R, Merad M, et al. Cancer and the gut microbiota: an unexpected link. Sci Transl Med. 2015;7:1–10. Scholar
  10. 10.
    Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers. 2015;1:15065.CrossRefGoogle Scholar
  11. 11.
    Ferreira MR, Muls A, Dearnaley DP, et al. Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. 2014;15(3):e139–47. Scholar
  12. 12.
    Montassier E, Batard E, Massart S, Gastinne T, Carton T, Caillon J, et al. 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation. Microb Ecol. 2014;67:690–9.CrossRefGoogle Scholar
  13. 13.
    Nigro G, Rossi R, Commere PH, Jay P, Sansonetti PJ. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe. 2014;15:792–8.CrossRefGoogle Scholar
  14. 14.
    Daillère R, Vétizou M, Waldschmitt N, et al. Enterococcus hirae and barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity. 2016;45:931–43. Scholar
  15. 15.
    Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342:967–70. Scholar
  16. 16.
    Scott TA, Quintaneiro LM, Norvaisas P, et al. Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell. 2017;169:442–456.e18.CrossRefGoogle Scholar
  17. 17.
    Zwielehner J, Lassl C, Hippe B, Pointner A, Switzeny OJ, Remely M, et al. Changes in human fecal microbiota due to chemotherapy analyzed by TaqMan-PCR, 454 sequencing and PCR-DGGE fingerprinting. PLoS One. 2011;6:e28654. Scholar
  18. 18.
    Stringer AM, Gibson RJ, Logan RM, et al. Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat. Exp Biol Med (Maywood). 2007;232:96–106. Scholar
  19. 19.
    Manichanh C, Varela E, Martinez C, Antolin M, Llopis M, Dor J, et al. The gut microbiota predispose to the pathophysiology of acute post-radiotherapy diarrhea. Am J Gastroenterol. 2008;103:1754–61. Scholar
  20. 20.
    Stringer AM, Gibson RJ, Bowen JM, Logan RM, Ashton K, Yeoh ASJ, et al. Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol. 2009;90:489–99. Scholar
  21. 21.
    Lin XB, Dieleman LA, Ketabi A, Bibova I, Sawyer MB, Xue H, et al. Irinotecan (CPT-11) irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats. PLoS One. 2012;7:e39764. Scholar
  22. 22.
    Bajic JE, et al. From the bottom-up: chemotherapy and gut-brain axis dysregulation. Front Behav Neurosci. 2018, 2018;12:104.
  23. 23.
    • Chang CW, Liu CY, Lee HC, et al. Lactobacillus casei variety rhamnosus probiotic preventively attenuates 5-fluorouracil/oxaliplatin-induced intestinal injury in a syngeneic colorectal Cancer model. Front Microbiol. 2018;15(9):983 An animal model study validating the positive protective impact of modulating the gut microbiome in the setting of 5FU based chemotherapy. Attenuation of intestinal injury seen as a result of probiotic supplementation.CrossRefGoogle Scholar
  24. 24.
    Din MO, Danino T, and Prindle A, et al (2016) Synchronized cycles of bacterial lysis for in vivo delivery Nature 536 81–85 https://
  25. 25.
    Kodawara T, Higashi T, Negoro Y, et al. The inhibitory effect of ciprofloxacin on the β-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G. Basic Clin Pharmacol Toxicol. 2016;118:333–7. Scholar
  26. 26.
    Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97(8):1028–34.CrossRefGoogle Scholar
  27. 27.
    Zhu XX, Yang XJ, Chao YL, Zheng HM, Sheng HF, Liu HY, et al. The potential effect of oral microbiota in the prediction of mucositis during radiotherapy for nasopharyngeal carcinoma. Epub 2017 Feb 7. EBioMedicine. 2017;18:23–31.CrossRefGoogle Scholar
  28. 28.
    Nam YD, Kim HJ, Seo JG, Kang SW, Bae JW. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS One. 2013;8:e82659.CrossRefGoogle Scholar
  29. 29.
    • Gerassy-Vainberg S, Blatt A, Danin-Poleg Y, et al. Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction. Gut. 2018;67:97–107 This study illustrates the impact of radiation on shifting the microbial niche toward dysbiosis. This was shown to highly correlating with radiation induced intestinal inflammation.CrossRefGoogle Scholar
  30. 30.
    Wang A, Ling Z, Yang Z, Kiela PR, Wang T, Wang C, et al. Gut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS One. 2015;10:e0126312.CrossRefGoogle Scholar
  31. 31.
    Neemann K, Freifeld A. Clostridium difficile-associated diarrhea in the oncology patient. J Oncol Pract. 2017;13(1):25–30. Scholar
  32. 32.
    Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233–9.CrossRefGoogle Scholar
  33. 33.
    Ferreira MR, Muls A, Dearnaley DP, Andreyev HJ. (2014). Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. doi:Google Scholar
  34. 34.
    Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol. 2014;32:189–225. Scholar
  35. 35.
    Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–84. Scholar
  36. 36•.
    Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7. This study provides backing evidence that quality and quantity of the gut microbiome impact responses to check point inhibitors.CrossRefGoogle Scholar
  37. 37.
    Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. Scholar
  38. 38.
    Frank M, Hennenberg EM, Eyking A, et al. Europe PMC Funders Group Europe PMC Funders Author Manuscripts TLR signaling modulates side effects of anticancer therapy in the small intestine. J Immunol. 2015;194:1983–95.
  39. 39.
    Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8.
  40. 40.
    Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–9. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Azhar Saeed
    • 1
  • Fariha Eshrat
    • 2
  • Shahid Umar
    • 3
  • Anwaar Saeed
    • 2
    Email author
  1. 1.Department of Pathology and Laboratory MedicineKansas University Medical CenterWestwoodUSA
  2. 2.Department of Medicine, Division of Medical OncologyKansas University Cancer CenterWestwoodUSA
  3. 3.Department of General SurgeryKansas University Medical CenterWestwoodUSA

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